Structural overview and perspectives of the nuclear receptors, a major family as the direct targets for small-molecule drugs.
Structural overview and perspectives of the nuclear receptors, a major family as the direct targets for small-molecule drugs.
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作为小分子药物直接靶标的主要家族核受体的结构概述和展望
DOI：
10.3724/abbs.2021001
复制
发表时间：
2022-01-25
影响因子：
3.7
通讯作者：
Wu D
中科院分区：
文献类型：
--
作者：
Li F;Song C;Zhang Y;Wu D
核受体(NRs)是一个与进化相关的转录因子家族，它们具有某些共同的结构特征，通过识别不同的反应元件来调节各种基因的表达。NRs在细胞的分化、增殖、存活和凋亡中起着重要的作用，在包括生长和代谢在内的许多生理活动中都是不可或缺的。因此，NRs的功能障碍与多种疾病密切相关，如糖尿病、肥胖症、不孕症、炎症、阿尔茨海默病、心血管疾病、前列腺癌和乳腺癌。同时，直接针对NRS的小分子药物已被广泛应用于上述疾病的治疗。本文综述了NR家族蛋白结构生物学研究的最新进展。与蛋白质数据库(PDB)30年来积累的数十个分离的DNA结合结构域(DBD)和一千多个分离的配体结合结构域(LBD)相比，到目前为止，只有少量的多结构域NR复合结构，揭示了具有变构信号转导功能的不同NR结构域的整合，或者NR与各种辅调节蛋白之间的详细相互作用。另一方面，关于几个孤儿NRs的结构信息仍然完全不可用，阻碍了对其功能的进一步了解。结构生物学新技术的快速发展必将帮助我们获得更全面的NR结构信息，激励人们发现具有超越经典LBD口袋的新结合部位和/或新的作用机制的新型NR靶向药物。
The nuclear receptors (NRs) are an evolutionarily related family of transcription factors, which share certain common structural characteristics and regulate the expressions of various genes by recognizing different response elements. NRs play important roles in cell differentiation, proliferation, survival and apoptosis, rendering them indispensable in many physiological activities including growth and metabolism. As a result, dysfunctions of NRs are closely related to a variety of diseases, such as diabetes, obesity, infertility, inflammation, the Alzheimer′s disease, cardiovascular diseases, prostate and breast cancers. Meanwhile, small-molecule drugs directly targeting NRs have been widely used in the treatment of above diseases. Here we summarize recent progress in the structural biology studies of NR family proteins. Compared with the dozens of structures of isolated DNA-binding domains (DBDs) and the striking more than a thousand of structures of isolated ligand-binding domains (LBDs) accumulated in the Protein Data Bank (PDB) over thirty years, by now there are only a small number of multi-domain NR complex structures, which reveal the integration of different NR domains capable of the allosteric signal transduction, or the detailed interactions between NR and various coregulator proteins. On the other hand, the structural information about several orphan NRs is still totally unavailable, hindering the further understanding of their functions. The fast development of new technologies in structural biology will certainly help us gain more comprehensive information of NR structures, inspiring the discovery of novel NR-targeting drugs with a new binding site beyond the classic LBD pockets and/or a new mechanism of action.
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DOI：
10.1073/pnas.2021287118
发表时间：
2021-02-09
影响因子：
11.1
作者：
de Vries RMJM;Meijer FA;Doveston RG;Leijten-van de Gevel IA;Brunsveld L
通讯作者：
Brunsveld L
影响因子：
64.5
作者：
Bledsoe, RK;Montana, VG;Xu, HE
通讯作者：
Xu, HE
影响因子：
4.8
作者：
Dhe-Paganon, S;Duda, K;Shoelson, SE
通讯作者：
Shoelson, SE
影响因子：
4.3
作者：
Bosica, Francesco;Andrei, Sebastian A.;O'Mahony, Gavin
通讯作者：
O'Mahony, Gavin
影响因子：
16
作者：
Bourguet, W;Vivat, V;Moras, D
通讯作者：
Moras, D